The present proposal is for the continued investigation of the etiology, pathogenesis, and pathobiology of ocular melanomas and retinoblastomas. It will utilized observations made and techniques developed in earlier research supported by this grant. In addition, new methods of investigation will be employed. The following objectives are proposed for the next five years: 1. Morphological studies employing parallel light microscopy, transmission electron microscopy, scanning electron microscopy, and freeze fracture techniques, as appropriate, to examine in detail the cell surface, intrinsic membrane structure, microtubular and fibrillar structure, cell junctions, and other ultrastructural details. These structures will be compared for the normal, "premalignant", dysplastic and various classifications of malignant cells for uveal malignant melanoma and retinoblastoma. Additional morphologic studies of inflammatory cells in malignant melanoma, sequence of degeneration of retinoblastoma and karyotypic studies in retinoblastoma and melanoma. 2. Molecular biology studies regarding the control of melanin synthesis in malignant and benign ocular pigmented cells; retinoid binding sites on retinoblastoma and melanoma cells; and radiosensitivity studies related to DNA-repair defects in retinoblastoma and melanoma patients. 3. Development of tumor models focusing on melanoma in the nude mouse, in addition to established melanoma and retinoblastoma cell lines; malignant transformation of ocular tissues with herpes simplex virus and nickel subsulfide. 4. Application of tumor models to clinical questions including the effect of enucleation on tumor cell dissemination and metastasis; the usefulness of adjunct radiotherapy; and retinoids in the treatment of retinoblastoma.